DESCRIPTION (Investigator's Abstract): The long-term goals of our research are to understand the mechanisms underlying growth and degeneration in the adult central nervous. Our general hypothesis is that the balance between growth and degenerative processes taking place under physiological or pathological conditions is critical to determine the changes in nervous- tissues occurring during normal conditions and as a result of insults or injuries. Our previous work has identified a number of mechanisms that are closely linked with growth and degenerative processes. In particular, all the conditions leading to neuronal pathology trigger the induction of several genes, including the gene for ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Polyamines have been linked with growth processes as well as with degenerative processes through their interactions with DNA, protein synthesis: calcium signaling and more recently with NA receptors. Several key questions have been raised by recent findings obtained during the tenure of our proposal: (i) What are the changes in polyamine levels in different cellular compartments following various forms of insults or injuries in adult and developing animals? (ii)What are the causes for the marked dissociations between seizure activity, ODC induction and neuronal pathology taking place during the postnatal period and exhibiting a major shift after the third postnatal week? (iii) Are the-between polyamines, NMDA receptors, calcium, DNA and protein synthesis important aspects of the polyamine functions in the CNS? The aims of the present proposal are to provide answers to these questions. Specifically we propose toe: (1) Determine the changes in polyamine levels and activity and expression of enzymes regulating polyamine levels in susceptible neuronal populations following excitotoxic lesions at different ages; (2) Evaluate the effect of inhibitors of the enzymes regulating polyamine levels (alone or in combination) on neuronal pathology elicited by excitotoxic agents; (3) Study the mechanisms involved in the dissociation between seizure activity, ODC induction, and neuronal pathology during the postnatal period; and (4) Study the effects of polyamines on NMDA receptor mediated responses in acute hippocampal slices. These studies should provide not only a better understanding of the cascade of events which follows neuronal injuries, but could also provide new ways to better control the degenerative processes occurring in a number of neurodegenerative diseases, while stimulating regenerative and growth processes.